PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Kidney in Pregnant Subjects and Fetus
The purpose of this study was to develop a physiologically based pharmacokinetic (PBPK) model predicting the pharmacokinetics (PK) of different compounds in pregnant subjects. This model considers the differences in tissue sizes, blood ﬂow rates, enzyme expression levels, glomerular ﬁltration rates, plasma protein binding, and other factors affected during pregnancy in both the maternal and fetal models. The PBPKPlus™ module in GastroPlus® was used to model the PK of cefuroxime and cefazolin. For both compounds, the model was ﬁrst validated against PK data in healthy non-pregnant volunteers and then applied to predict pregnant groups PK. The model accurately described the PK in both non-pregnant and pregnant groups and explained well differences in the plasma concentration due to pregnancy. The fetal plasma and amniotic ﬂuid concentrations were also predicted reasonably well at different stages of pregnancy. This work describes the use of a PBPK approach for drug development and demonstrates the ability to predict differences in PK in pregnant subjects and fetal exposure for compounds excreted renally. The prediction for pregnant groups is also improved when the model is calibrated with postpartum or nonpregnant female group if such data are available.
By Ke Xu Szeto, Maxime Le Merdy, Benjamin Dupont, Michael B. Bolger, and Viera Lukacova